The use of combinatorial techniques to generate libraries of chemical and/or biological compounds is known in the art. Once these libraries have been generated, it is necessary to screen or characterize the compounds to determine if the desired properties are present, i.e. physical, chemical and/or biological properties, for example. However, most techniques developed for screening and characterization of combinatorial libraries are sequential, involve sample preparation or sample transfer steps, and are generally labor-intensive, time-consuming and expensive for large libraries or arrays of several compounds.
What is needed in the art are apparatus and methods for high-throughput multiple parallel synthesis, followed by high-throughput screening and characterization of individual components in arrays or combinatorial libraries. In addition, these techniques should preferably be easily adapted to microscale techniques. Further, these techniques and apparatuses should be adaptable not only to areas where combinatorial chemistry is commonly used, such as pharmaceutical, biotechnology, and agrochemical research, but also to a broad range of disciplines, including catalysis and polymer chemistry.
Methods and apparatus for screening diverse arrays of materials in parallel using infrared imaging techniques are described in WO 98/15813. WO 97/32208 describes a catalyst testing process and apparatus, which includes methods and apparatus for parallel testing of catalysts. Despite these developments, there remains a need for techniques for the synthesis, screening, and characterization of individual compounds of a combinatorial library in the same array in a highly parallel fashion, without requiring the transfer of compounds from the array for analysis. This invention answers this need.
Moreover, the analysis of physical properties such as viscosity have yet to be adapted to combinatorial arrays, in a highly parallel manner and as applied to a broad range of compounds. WO 98/15501 describes systems and methods for characterization of materials and combinatorial libraries with mechanical oscillators. However, it does not appear that these methods would be generally adaptable to compounds other than liquids. U.S. Pat. No. 5,710,374 describes an electronic viscometer, and U.S. Pat. No. 5,889,351 describes a device for measuring viscosity and a device for measuring characteristics of fluid, but neither of these is designed or adapted for analysis of compounds other than liquids, or for combinatorial analysis of arrays. Work on electrostrictive principles has been reported in R. E. Pelrine et al., Proceedings of the 10th Annual IEEE International Workshop on Microelectrode Mechanical Systems, Nagoya, Japan, pp. 238-243. However, this work has not been adapted for combinatorial chemistry. Also recently reported in WO 98/15501 is a combinatorial method to measure the molecular weight and molecular weight distribution of polystyrene in situ, using an array of vibrating reeds. However, this vibrating reed technique measures only the viscosity of the polymer mixture in solution. Accordingly, what is needed in the art are combinatorial techniques for measuring the viscosity of samples in arrays, and techniques for measuring viscosity which are not restricted to liquids. This invention answers this need.
Also needed in the art are combinatorial techniques for measuring the comonomer content of compounds. Although WO 97/37953 describes mass-based encoding and qualitative analysis of combinatorial libraries, these techniques are used primarily as a means for encoding, and are not adapted to quantitative analysis of the comonomer content of compounds or incorporation of a reagent, for compounds synthesized in combinatorial libraries. Polymer composition has not been investigated using radiography. Cracks and formations in polymer films have been investigated by diffusing a radiolabeled gas or liquid into a preformed polymer and scanning the sample using radiography. (See e.g., Figge, K. et al., Deut. lebensm-Rundsch 66(9):281-9 (1970), Bellazzini, R. et al., Nucl. Instrum. Methods Phys. Res. Sect. A A251(1):196-8 (1986), Mysak, F. et al., Izotoptechnika, 14(1-2):27-28 (1971), Bekman, I. N., et al. Radiokhimiya 28(2):222-229 (1986), and Kocbynka, D. et al., Radioisotopy 8(6):860-1 (1967)). Radiography has been used extensively for the rapid screening of biological samples. Yet, radiography has not been generally extended for the analysis of a variety of compounds. For example, polymer compositions (e.g., comonomer content) have never been investigated using radiography. Therefore, what is needed in the art is a technique for screening and characterization of combinatorial libraries that provides a qualitative and/or quantitative determination of comonomer content or incorporation of a reagent. This invention answers this need.
There have also been some developments in the characterization and screening of combinatorial libraries. For example, in-situ resonance enhanced multiphoton ionization (REMPI) spectroscopy has been demonstrated for rapid characterization of gaseous products produced by arrays of dehydrogenation catalysts. (S. M. Senkan, et al., Angew. Chem. Intl. Ed, 38:791 (1999)). In addition, techniques for the parallel screening of heterogeneous oxidation catalysts have been described in WO 98/15813 and WO 97/32208. Techniques for simultaneously measuring-catalyst activity and the molecular weight of the forming polymer in an array of 48 reactors has also been reported. (See U.S. Pat. No. 5,762,881 (1998)). Although these techniques have increased throughput in many cases, the relatively large reactor volume of the arrays and the capital investment to purchase new reactor blocks restricts the use of these arrays.
Although methods and apparatus for surface diagnostics have been reported in U.S. Pat. No. 4,733,073, these methods have not yet been adapted to the analysis of combinatorial libraries. U.S. Pat. No. 5,959,297 teaches mass spectrometers and methods for rapid screening of different materials. However, these methods appear to be slow and are not run under realistic process conditions. Therefore, what is needed in the art are mass spectrometry techniques which are run under realistic process conditions. Similarly, although method and apparatus for modulated differential analysis has been described in U.S. Pat. No. 5,224,775 and methods and apparatus for spatially resolved modulated differential analysis have been described in U.S. Pat. No. 5,248,199 these methods have not yet been adapted to the microscale or to combinatorial techniques. Methods for mass spectrometry, adapted to combinatorial chemistry are needed. This invention answers this need.
Adapting these combinatorial chemistry techniques to the microscale is particularly a challenge in fields such as catalysis and polymer chemistry. Catalytic olefin polymerization, for example, is sensitive to small variations in conditions and has rarely been attempted using microscale combinatorial techniques. However, if microscale combinatorial techniques could be adapted for use in these fields, this would significantly facilitate research and development, with the advantages of lower reagent costs, higher throughput, and greater efficiency.
There have been some attempts to adapt combinatorial synthesis techniques to the field of catalysis and polymer chemistry. In one case, combinatorial hydrothermal syntheses for zeolites was reported. (See D. E. Akporiaye, et al., Angew. Chem. Intl. Ed., 37:609 (1998) and J. Klein, et al., Angew. Chem. Intl. Ed., 37:3369 (1998)). However, high-throughput methods for screening and characterizing the components of the library, in the same apparatus used for the synthesis have not been described.
The combinatorial synthesis and analysis of supported and unsupported organometallic compounds and catalysts (e.g. homogeneous catalysts) has been described in WO 98/03521. In one embodiment, the substrate has an array of materials fixed thereon and the detector has X-Y motion. In another embodiment, the detector is fixed and the substrate having an array of materials thereon has R-θ motion. WO 98/15969 describes mass spectrometry and methods for rapid screening of libraries of different materials. However, for large combinatorial libraries, these sequential methods can be time-consuming and expensive. In addition, these methods are not adapted such that the compounds could be synthesized in the same array used for analysis.
What is needed are techniques which could efficiently screen and characterize libraries of polymers in a high-throughput manner. Further, these methods for screening and characterizing the polymer should preferably be adaptable to the microscale. This invention answers this need.
Accordingly, what is needed is a workstation, apparatus, and methods adapted for any combination of combinatorial synthesis, screening and/or characterization steps, without requiring excessive sample handling or transfer of components from the array between these steps. Preferably these methods will be non-consumptive, highly parallel, generally adaptable to the microscale, and generally applicable in many fields. Preferably, these techniques could be automated, such that the same array is moved between several different stations or analytical instruments. This invention answers this need.